The Role of the Airway Epithelium in the Modulation of Bronchial Smooth Muscle Responsiveness

Asthma is characterised clinically by bronchial hyperreactivity and bronchial spasm, and histologically by thickened oedematous airways, which show extensive epithelial destruction. In asthmatic patients, the degree of airway hyperreactivity correlates with damage to the epithelium. In vitro studies using animal models have shown that removal of the airway epithelium renders the bronchial smooth muscle more responsive to contractile agents, and diminishes the relaxing effect of beta-adrenergic agonists. It has been proposed that there is an epithelium-derived relaxing factor which diffuses from the epithelial cell and alters the responsiveness of the underlying bronchial smooth muscle. The aims of the present study were (i) to determine whether the airway epithelium can modulate the effect of contractile and relaxing agonists, (ii) to investigate whether such an effect shows heterogeneity between different airways, different species and different pharmacological agents, (iii) to investigate the potential role of the metabolites of arachidonic acid, prostaglandins and leukotrienes, and (iv) to use these data to draw conclusions about the distribution, mechanism of action, and physiological role of the proposed epithelium-derived relaxing factor or factors

Studies on the renal effects of bradykinin in anesthetized dogs function and regional extravasation of albumin

The kidney is a primary regulator of body fluid composition and volume.The particular architecture and functional properties of the tubular and vascular elements of the kidney and their interaction allows for the selective excretion or retention of various solutes and even of water itself.The mechanisms leading to certain functional responses are extremely complex and not yet fully understood but are in large part regulated by hormones acting at specific locations in the kidney. Of the many hormones involved we chose to study bradykinin because it is normally produced in the kidney, it may be involved in pathophysiological processes (eg. hypertension and inflammation) and is certainly affected by common pharmacotherapeutic interventions. We first present studies in which dogs, infused with either hypotonic saline or an isotonic solution of urea, received a small dose of bradykinin via the renal artery.The demonstration of dissociable diuretic and natriuretic effects in these conditions supports the idea that bradykinin acts in the distal segments of the nephron. We then describe the development of a technique allowing us to determine regional changes in the extravasation of albumin from the renal microcirculation as well as changes in tissue water content. We present studies validating the use of Evans Blue dye as a marker for albumin and experiments that validate the assumption that the dye we measure is indeed extravascular. We show that the distribution between renal zones is very heterogeneous and changes under various conditions of altered renal function. We applied the technique to identify renal vascular sites of action of bradykinin. Furthermore, the role of receptor subtypes in this response was determined using selective receptor antagonists. Intrarenal bradykinin infusion is shown to exclusively change cortical albumin extravasation. We also demonstrate completely different profiles of two different angiotensin converting enzyme inhibitors (products known to reduce kinin degradation) on function and albumin extravasation. Finally, the effects on albumin extravasation was determined in dogs subjected to renal ischemia reperfusion injury since this common pathophysiological condition is known to involve a localized inflammatory reaction (perhaps involving bradykinin). This did not appear to be the case. We submit this work in the hope that it may provide insight into the renal actions of bradykinin as well as on the mechanisms regulating renal function in general